In medical care, it goes without saying that a therapeutic agent for infectious diseases is indispensable. At present, a number of therapeutic agents for infections such as antibiotics and synthetic antibacterial agents are provided to be used in medical care.
However, currently, an antibacterial agent which is mainly provided as therapeutic agent for infections has in fact an unavoidable problem; appearance of drug resistant bacteria. That is, a new antibacterial agent leads to produce a new drug resistant bacterium, and such a sarcastic state continues until now.
For example, tuberculosis occupies the first position of a death rate among single infectious diseases, and its increasing tendency becomes a worldwide problem. Further, a drug resistant bacterium having resistance to almost all antibiotics has been confirmed, and this problem has been obvious.
Recently, it has been revealed that granulysin, which is a molecule expressed in Natural Killer cells (NK cell) or Cytotoxic T Lymphocytes (CTL), has direct ability to kill and injure bacteria such as Mycobacterium tuberculosis [Stenger, S. et al., Science 282, 121-125 (1998)].
Granulysin is produced as a precursor of 15K and, thereafter, processed into 9K in a cytotoxic granule. It is known that this 9K granulysin has antibacterial activity (Pena, S. V. et al., J. Immunol, 158, 2680-2688 (1997)).
However, it is necessary to use a perforin, which is a molecule derived from the same cytotoxic intragranule, to allow 9K granulysin to show the antibacterial activity. This is because perforin perforates a target cell, 9K granulysin enters into the cell therethrough, and 9K granulysin introduced into the target cell kills and injures an infecting bacterium in the cell [Stenger, S. et al., Science 282, 121-125 (1998)].
Accordingly, it is necessary to administer perforin simultaneously to use 9K granulysin as a therapeutic agent for infections. However, as described above, perforin shows cytotoxicity (Pena, S. V. et al., J. Immunol, 158, 2680-2688 (1997)), and therefore its administration may cause considerable side effects.
In addition, the present inventors produced 9K granulysin transgenic mouse and 15K granulysin transgenic mouse, then intravenously administered 5×105 CFU of H37Rv Mycobacterium tuberculosis through tail vein in each mouse and a wild-type control mouse respectively, and after 4 weeks, measured the numbers of Mycobacterium tuberculosis in lungs of each mouse, and confirmed that the number of Mycobacterium tuberculosis in the lung of 15K granulysin transgenic mouse is more reduced than that of 9K granulysin transgenic mouse with a statistically significant difference (p<0.05; Student's t Test). Thus, the present inventors are the first to find that 15K granulysin has significantly stronger killing effect and suppressing effect on Mycobacterium tuberculosis in vivo than 9K granulysin. In addition, the result suggests that 9K Granulysin has very weak suppressing effect on Mycobacterium tuberculosis in vivo.